Organic compounds selectively substituted with fluorine have utility as drugs, agrichemicals, medical imaging agents, and high polarization additives for ferroelectric liquid crystal compositions, as well as in many other applications. Fluorinated steroids and drugs are often more potent than their unsubstituted analogs due to increased lipophilic behavior, suppression of undesired metabolic reactions, and reduced binding to serum proteins. (See, e.g., J. A. Katzenellenbogen et al., J. Org. Chem. 49, 4900 (1984).) Chiral ferroelectric liquid crystal compounds having a fluorine atom at the chiral center exhibit larger spontaneous polarizations and greater smectic character than their hydrocarbon analogs. (See, e.g., H. Nohira et al., Mol. Cryst. Liq. Cryst. 180B, 379, 385 (1990).)
The preparation of such selectively fluorinated materials poses special difficulties due to a tendency for hydrogen fluoride elimination under the conditions conventionally used to prepare these materials. One commonly used strategy is to replace a hydroxyl group (in a starting compound) with a fluorine atom, but this is not an easy transformation since carbonium ion rearrangements and dehydration to an olefin can occur. (See, e.g., W. J. Middleton, J. Org. Chem. 40, 574 (1975).)
Such side reactions can be minimized by the use of DAST (diethylaminosulfur trifluoride) as the fluorinating reagent. DAST fluorinations can be carried out under mild conditions, making DAST more convenient to use than some other fluorination reagents such as sulfur trifluoride. (See, e.g., M. Hudlicky, Organic Reactions, volume 35, page 513, John Wiley and Sons, New York (1988).) However, DAST is not commercially available and is costly to produce (due, e.g., to the need for specialized preparation and handling equipment), and the yields obtained using DAST are often only moderate.
Selectively fluorinated materials have also been prepared from their hydroxyl-functional equivalents (primary and secondary alcohols) using perfluoroalkanesulfonyl fluorides and strong bases in organic solvent (as described by B. Benua-Skalmowski and H. Vorbrueggen in Tetrahedron Letters 36 (15), 2611 (1995), as well as in International Patent Publication No. WO 96/13474 (Vorbrueggen) and U.S. Pat. No. 5,760,255 (Vorbrueggen et al.)). This method has involved the use of 2 to 3 equivalents of base, with addition of the perfluoroalkanesulfonyl fluoride to a premix of alcohol and base.
However, there is a continuing need in the art for a selective fluorination process that is useful on an industrial scale. Such a process should not only be cost effective and capable of being carried out using common multipurpose industrial equipment, but should also be able to consistently provide good to excellent yields under the variable conditions commonly encountered in a factory setting.